Phosphorylation and mRNA Splicing of Collapsin Response Mediator Protein-2 Determine Inhibition of Rho-associated Protein Kinase (ROCK) II Function in Carcinoma Cell Migration and Invasion

Morgan-Fisher, Marie; Couchman, John R.; Yoneda, Atsuko

doi:10.1074/jbc.m113.505602

Cited by 16 publications

(14 citation statements)

References 56 publications

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“…Given our results showing that Fasudil treatment inhibited p‐CRMP‐2 (Thr514) expression in the CNS of EAE mice, we speculate that Fasudil protects neurons and synapses from inflammation‐induced damage in EAE mice, probably through suppressing CRMP‐2 phosphorylation. Besides, the current data also demonstrate that CRMP‐2‐dependent regulation of ROCK II activity is partially regulated by GSK‐3β, suggesting that phosphorylation of CRMP‐2 by GSK‐3β sensitively regulates the CRMP‐2 and ROCK II interaction and thereby influences ROCK II‐dependent cellular functions . GSK‐3β activation mediated Nogo‐66‐induced inhibition of neurite outgrowth in vitro .…”

Section: Discussionsupporting

confidence: 60%

Changes of synapses in experimental autoimmune encephalomyelitis by using Fasudil

Chen

Zhang

et al. 2016

Wound Repair Regeneration

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The ROCK signaling pathway is involved in numerous fundamental cellular functions such as cell migration, apoptosis, inflammatory responses, and neurite outgrowth. Previous studies demonstrate that Fasudil exhibited therapeutic potential of experimental autoimmune encephalomyelitis (EAE) possibly through immune-modulation and anti-inflammation. In this study, we observed the effect of Fasudil on synaptic protection of EAE mice. Fasudil ameliorated the clinical severity of EAE and inhibited Rho kinase (ROCK), especially ROCK II, in brain and spinal cord of EAE mice. Protein extracts from spinal cord of Fasudil-treated EAE mice promoted the formation of neurite outgrowth when co-cultured with primary neurons, indicating that peripheral administration of Fasudil can enter the central nervous system (CNS) and exhibited its biological effect on the formation of neurite outgrowth. Synapse-related molecule synaptophysin was enhanced, and CRMP-2, AMPA receptor, and GSK-3β were declined in spinal cord of Fasudil-treated mice. Neurotrophic factor BDNF and GDNF as well as immunomodulatory cytokine IL-10 in spinal cord were elevated in Fasudil-treated mice, while inflammatory cytokine IL-17, IL-1β, IL-6, and TNF-α were obviously inhibited, accompanied by the decrease of inflammatory M1 iNOS and the increase of anti-inflammatory M2 Arg-1, providing a microenvironment that contributes to synaptic protection. Our results indicate that Fasudil treatment protected against synaptic damage and promoted synaptic formation, which may be related with increased neurotrophic factors as well as decreased inflammatory microenvironment in the CNS of EAE mice.

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Section: Discussionsupporting

confidence: 60%

Changes of synapses in experimental autoimmune encephalomyelitis by using Fasudil

Chen

Zhang

et al. 2016

Wound Repair Regeneration

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“…7). Residues 472-564 of CRMP5 in the C-terminus include multiple putative phosphorylation sites, which can be regulated by CDK-5, GSK-3β, or ROCK II, causing dissociation with tubulin heterodimers and kinesin (Morgan-Fisher et al, 2013). Additional research has indicated that CRMPs regulate neurite outgrowth by promoting microtubule polymerization and cargo transportation.…”

Section: Discussionmentioning

confidence: 99%

Spastin Interacts with CRMP5 to Promote Neurite Outgrowth by Controlling the Microtubule Dynamics

Zhang²,

Chen

et al. 2018

Developmental Neurobiology

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Changing the microtubule dynamics is sufficient to alter the axon and dendrite specification and development. Spastin participates in the growth and regeneration of neurites by severing microtubules into small segments, and collapsin response mediator protein 5 (CRMP5) provides structural support and serves as a track for cargo transport by promoting microtubule polymerization. Nevertheless, how spastin and CRMP5 cooperate to regulate neurite outgrowth by controlling the microtubule dynamics needs to be elucidated. In our present study, spastin interacted with CRMP5 in vitro and in vivo. The binding domains for the spastin and CRMP5 interaction were the N‐terminal fragment of spastin (residues 270–328) and the C‐terminal fragment of CRMP5 (residues 472–564). Spastin and its truncation mutants, including the microtubule‐binding domain (MTBD) and ATPases associated with diverse cellular activities (AAA) domain, were necessary for the severing of microtubules. Furthermore, we demonstrated that microtubule polymerization of CRMP5 interfered with the microtubule‐severing function of spastin. Knocking down either spastin or CRMP5 inhibited neurite outgrowth in hippocampal neurons. However, co‐transfected spastin and CRMP5 promoted the outgrowth of neurites including dendrites and axons. Taken together, our data support a model in which the spastin interaction with CRMP5 promotes neurite outgrowth by controlling the microtubule dynamics.

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“…CRMP-1 is suggested to be a cancer suppressor [17,31,32], while LCRMP-1 functions to promote cancer metastasis [19,33,34]. CRMP-2 was suggested as a prognostic marker and candidate therapeutic target in NSCLC and colorectal carcinoma [20,[35][36][37]. Regarding DRP5, its neuronal autoantibody was reported to be related with patients at risk for lung carcinoma [22,38,39].…”

Section: Discussionmentioning

confidence: 99%

DRP5 is involved in cancer cell growth and predicts poor prognosis in human osteosarcoma

et al. 2017

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Osteosarcoma is an extremely aggressive primary malignant bone tumor of childhood. Collapsin response mediator proteins (CRMPs), which are highly expressed in the developing nervous system, were recently shown to be associated with cancer development. However, the relationship between DRP5 (CRMP5) and osteosarcoma has not been evaluated. In this study, we investigated the role of DRP5 in the regulation of osteosarcoma growth. DRP5 mRNA and protein levels were significantly upregulated in human osteosarcoma cell lines and associated with increased migration and invasion. Genetic knockdown of DRP5 markedly suppressed the expression of matrix metalloproteinase (MMP)‐2 and MMP‐9. DRP5 silencing significantly inhibited osteosarcoma cell growth in vitro and in a xenograft mouse model in vivo. Microarray immunohistochemical analysis of osteosarcoma specimens and Kaplan–Meier analysis showed that patients with high DRP5 protein expression had shorter overall survival than those with low DRP5 levels. Taken together, these results suggest that DRP5 plays a critical role in the regulation of osteosarcoma and could be a potential therapeutic target and prognostic factor in osteosarcoma.

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Phosphorylation and mRNA Splicing of Collapsin Response Mediator Protein-2 Determine Inhibition of Rho-associated Protein Kinase (ROCK) II Function in Carcinoma Cell Migration and Invasion

Cited by 16 publications

References 56 publications

Changes of synapses in experimental autoimmune encephalomyelitis by using Fasudil

Changes of synapses in experimental autoimmune encephalomyelitis by using Fasudil

Spastin Interacts with CRMP5 to Promote Neurite Outgrowth by Controlling the Microtubule Dynamics

DRP5 is involved in cancer cell growth and predicts poor prognosis in human osteosarcoma

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